L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products

L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. Their effect on endothelial dysfunction in hypertension was studied after treatment with either 200 mg/kg of L-carnitine or propionyl-L-carnitine during 8 weeks of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Endothelial function was assessed in aortic rings by carbachol-induced relaxation (CCh 10(-8) to 10(-4) M) and factors involved were characterized in the presence of the inhibitors: L-NAME, indomethacin, the TXA2/PGH2 Tp receptor antagonist ICI-192,605 and the thromboxane synthetase inhibitor-Tp receptor antagonist, Ro-68,070. The effect on phenylephrine-induced contractions was also observed. To identify the nature of vasoactive COX-derived products, enzyme-immunoassay of incubation media was assessed. Involvement of reactive oxygen species was evaluated by incubating with superoxide dismutase and catalase. Nitric oxide production was evaluated by serum concentration of NO2+NO3.Treatment with both compounds improved endothelial function of rings from SHR without blood pressure change. Propionyl-L-carnitine increased NO participation in WKY and SHR. L-carnitine reduced endothelium-dependent responses to CCh in WKY due to an increase of TXA2 production. In both SHR and WKY, L-carnitine enhanced concentration of PGI2 and increased participation of NO. Results in the presence of SOD plus catalase show that it might be related to antioxidant properties of L-carnitine and propionyl-L-carnitine. Comparison between the effect of both compounds shows that both may reduce reactive oxygen species and increase NO participation in endothelium-dependent relaxations in SHR. However, only L-carnitine was able to increase the release of the vasodilator PGI2 and even enhanced TXA2 production in normotensive rats.     

Reduced connexin-43 expression in the aorta of prehypertensive rats

Genetic component represents an important factor in the development of hypertension, which is known to be associated with changes in expression of vascular gap junction protein connexin 43 (Cx43). The aim of the study was to examine the distribution and expression of Cx43 in the aortic endothelium of adult normotensive Wistar rats (W), borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR). Rings of the thoracic aorta were processed for immunofluorescence and Western blot analysis of endothelial Cx43 and for electron microscopy. Both, BHR and SHR exhibited significantly increased blood pressure vs. W (132+/-2 mm Hg and 185+/-3 mm Hg vs. 110+/-2 mm Hg). Reduced Cx43 immunofluorescence was observed in the endothelium of BHR and these alterations were more pronounced in SHR. Western blot analysis showed significant suppression of Cx43 expression in the aorta of both BHR (p<0.05) and SHR (p<0.001) vs. W. Electron microscopy revealed local subcellular alterations of interendothelial connections in BHR including extended tight junctions. These alterations were more frequent and marked in SHR. The results indicate that connexin 43 expression is reduced in the aortic endothelium already in prehypertensive period, which may affect cell-to-cell communication and thus participate in acceleration of hypertensive disease.     

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Activation of AMP-activated protein kinase (AMPK) induces vasorelaxation in arteries from healthy animals, but the mechanisms coordinating this effect are unclear and the integrity of this response has not been investigated in dysfunctional arteries of hypertensive animals. Here we investigate the mechanisms of relaxation to the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) in isolated thoracic aorta rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Although AICAR generated dose-dependent (10(-6)-10(-2) M) relaxation in precontracted WKY and SHR aortic rings with (E(+)) or without (E(-)) endothelium, relaxation was enhanced in E(+) rings. Relaxation in SHR E(+) rings was also enhanced at low [AICAR] (10(-6) M) compared with that of WKY (57 ± 8% vs. 3 ± 2% relaxation in SHR vs. WKY E(+)), but was similar and near 100% in both groups at high [AICAR]. Pharmacological dissection showed that the mechanisms responsible for the endothelium-dependent component of relaxation across the dose range of AICAR are exclusively nitric oxide (NO) mediated in WKY rings, but partly NO dependent and partly cyclooxygenase (COX) dependent in SHR vessels. Further investigation revealed that ACh-stimulated COX-endothelium-derived contracting factors (EDCF)-mediated contractions were suppressed by AICAR, and this effect was reversed in the presence of the AMPK inhibitor Compound C in quiescent E(+) SHR aortic rings. Western blots demonstrated that P(Thr(172))-AMPK and P(Ser(79))-acetyl-CoA carboxylase (indexes of AMPK activation) were elevated in SHR versus WKY E(+) rings at low AICAR (～2-fold). Together these findings suggest that AMPK-mediated inhibition of EDCF-dependent contraction and elevated AMPK activation may contribute to the enhanced sensitivity of SHR E(+) rings to AICAR. These results demonstrate AMPK-mediated vasorelaxation is present and enhanced in arteries of SHR and suggest that activation of AMPK may be a potential strategy to improve vasomotor dysfunction by suppressing enhanced endoperoxide-mediated contraction and enhancing NO-mediated relaxation.     

Vascular function and nitric oxide production in chronic social-stress-exposed rats with various family history of hypertension.

The study investigated the effect of chronic crowding stress on vascular function and nitric oxide (NO) production in rats with various family history of hypertension. Wistar (W), wBHR (offspring of W dams and spontaneously hypertensive sires), sBHR (offspring of spontaneously hypertensive dams and W sires) and spontaneously hypertensive rats (SHR) were used. Twelve-week-old males were divided into the control or crowded group for eight weeks. Basal blood pressure (BP, determined by tail-cuff plethysmography) of W, wBHR, sBHR and SHR rats was 112 +/- 3, 129 +/- 2, 135 +/- 2 and 187 +/- 3 mmHg, respectively. Crowding increased BP and reduced aortic NO synthase activity only in sBHR and SHR rats, without alterations in hypothalamic NO production. Acetylcholine-induced vasorelaxation of the femoral artery of stress-exposed rats was improved in W, unaltered in wBHR and sBHR and reduced in SHR. Crowding reduced serotonin-induced vasoconstriction in W and wBHR rats but had no effect in sBHR and SHR rats. In conclusion, the results suggest that crowded offspring of normotensive mothers were able to modify their vascular function in order to maintain BP at normal levels. On the other hand, offspring of hypertensive mothers were unable of effective adaptation of vascular function in stressful conditions resulting in gradual development of hypertension.     

Hypertension alters the participation of contractile prostanoids and superoxide anions in lipopolysaccharide effects on small mesenteric arteries

The involvement of cyclooxygenase-2 (COX-2)-derived products and superoxide anion in the effect of lipopolysaccharide in noradrenaline (NA)-induced contraction was investigated in small mesenteric arteries (SMA) from normotensive, Wistar Kyoto (WKY), and spontaneously hypertensive (SHR) rats. In WKY, lipopolysaccharide (10 microg/ml, 1 and 5 h) only inhibited the NA response (0.1-30 microM) in the presence of dexamethasone (1 microM), indomethacin (10 microM), the selective COX-2 inhibitor, NS 398 (10 microM), and the TXA(2)/PGH(2) receptor antagonist, SQ 29,548 (10 microM) but not of superoxide dismutase (SOD, 100 U/ml). In SHR, lipopolysaccharide inhibited the NA response by itself; this inhibition was potentiated by dexamethasone, indomethacin, NS 398, SQ 29,548 and SOD. The effect of lipopolysaccharide plus indomethacin, NS 398 or SQ 29,548 was higher in SMA from WKY than SHR only after 1 h lipopolysaccharide incubation. N(G)-nitro-L-arginine methyl ester (100 microM) and endothelium removal abolished the indomethacin-induced potentiatory effect of lipopolysaccharide in both strains. Endothelium removal also abolished the SOD potentiatory effect in SMA from SHR. Lipopolysaccharide increases COX-2 expression to a similar level in both strains and iNOS expression in a greater extent in SHR; these increases were reduced by dexamethasone. These results indicate: 1) lipopolysaccharide induces the endothelial production of contractile prostanoids from COX-2 in SMA, probably to compensate the increase in NO from iNOS; 2) the production of prostanoids in the presence of lipopolysaccharide seems to be greater in normotensive than hypertensive rats only after lipopolysaccharide short incubation times; 3) endothelial production of O(2)(.-) contributes to counteract depression of NA contraction caused by lipopolysaccharide only in SHR.     

原发性高血压患者红细胞抗高血压因子对高血压...

The effects of antihypertensive factor (AHF) from erythrocytes of essential hypertensive human subjects on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), Wistar-Kyoto rats (WKY) and Wistar rats were examined. Single intraperitoneal injection of AHF (1.6 mg/kg body weight) resulted in a significant decrease in SBP of SHR and RHR. At 10 min postinjection, AHF lowered the SBP in SHR by 34.0 mmHg. SBP recovered to the original level at 3 h. The maximal decrease of SBP in RHR by 92.5 mmHg was at 24h postadministration and the SBP did not recover until the 9th day. When AHF was administered via femoral vein (0.8 mg/kg body weight), the maximal decrease values of the SBP and the DBP were 42.8 and 48.2 mmHg in SHR at 12 min and 38.3 and 42.5 mmHg in RHR at 25 min postinjection respectively. The DBP in Wistar rats decreased considerably (from 96.7 +/- 12.9 to 83.3 +/- 11.7 mmHg) at 5 min postadministration of AHF, but no effect on DBP in WKY rats was observed. The depressor effect of AHF on SBP in RHR was dose-dependent. AHF could also antagonize the pressor effect of norepinephrine in Wistar rats.     

Exposure to stress differential vascular adaptive response in spontaneously hypertensive and Wistar rats: Role of nitric oxide, and prehypertensive and hypertensive states

Stress-induced vascular adaptive response in SHR was investigated, focusing on the endothelium. Noradrenaline responses were studied in intact and denuded aortas from 6-week-old (prehypertensive) and 14-week-old (hypertensive) SHR and age-matched Wistar rats submitted or not to acute stress (20-min swimming and 1-h immobilization 25 min apart), preceded or not by chronic stress (2 sessions 2 days apart of 1-h day immobilization for 5-consecutive days). Stress did not alter the reactivity of denuded aorta. Moreover, no alteration in the EC50 values was observed after stress exposure. In intact aortas, acute stress-induced hyporeactivity to noradrenaline similar between strains at both age. Chronic stress potentiated this adaptive response in 6- and 14-week-old Wistar but not in 6-week-old SHR, and did not alter the reactivity of 14-week-old SHR. Maximum response (g) in intact aortas [6-week-old: Wistar 3.25+/-0.12, Wistar/acute 1.95+/-0.12*, Wistar/chronic 1.36+/-0.21*(+), SHR 1.75+/-0.11, SHR/acute 0.88+/-0.08*, SHR/chronic 0.85+/-0.05*; 14-week-old: Wistar 3.83+/-0.13, Wistar/acute 2.72+/-0.13*, Wistar/chronic 1.91+/-0.19*(+), SHR 4.03+/-0.17, SHR/acute 2.26+/-0.12*, SHR/chronic 4.10+/-0.23; inside the same strain: *P < 0.05 relate to non-stressed rat, +P < 0.05 related to acute stressed rat; n = 6-18]. Independent of age and strain, L-NAME and endothelium removal abolished the stress-induced aorta hyporeactivity. CONCLUSION: The vascular adaptive response to stress is impaired in SHR, independently of the hypertensive state. Moreover, this vascular adaptive response is characterized by endothelial nitric oxide-system hyperactivity in both strains.     

Vascular effects of 15-F2t-isoprostane in spontaneously hypertensive rats

F2-isoprostanes are a family of compounds derived from arachidonic acid by free radical-catalyzed peroxidation. Among F2-isoprostanes, 15-F2t-IsoP is a vasoconstrictor in animal and human vascular beds. Several recent studies found increased 15-F2t-IsoP levels in animal models of hypertension. However, no data is available on the vascular effect of 15-F2t-IsoP in such models. The contractile responses of 15-F2t-IsoP (10(-9) to 3 x 10(-5) mol/L) were tested on rat thoracic aortic rings in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. The contraction induced by 15-F2t-IsoP was not significantly different in aortic rings from WKY rats and SHR (Emax 139% +/- 5% vs. 134% +/- 6%, respectively) and was mediated through thromboxane A2-prostaglandin H2 receptor activation as shown by the rightward shift of the concentration-contraction curves in presence of GR 32191, a specific thromboxane A2-prostaglandin H2 receptor antagonist. Endothelial denudation increased the maximal contraction compared to intact rings induced by 15-F2t-IsoP in both WKY rats (170% +/- 20% vs. 139% +/- 5%, p < 0.05) and SHR (194% +/- 11% vs. 134% +/- 6%, p < 0.01), whereas pretreatment with Nomega-nitro-L-arginine (10(-4) mol/L) or with indomethacin (10(-5) mol/L) increased the maximal contraction to 15-F2t-IsoP in WKY rats but not in SHR. SHRs treated with an angiotensin-converting enzyme inhibitor, enalapril, for four weeks showed decreased maximal contraction to 15-F2t-IsoP in vessels with and without endothelium compared with untreated SHR. In conclusion, 15-F2t-IsoP-induced vasoconstriction is similar in SHR compared with WKY rats. Endothelium modulates 15-F2t-IsoP contraction in both strains. However, whereas this effect is mediated through nitric oxide- and cyclooxygenase-dependent pathways in WKY rats, other mediators are implicated in SHR.     

Delayed development of hypertension and increased aortic relaxation in spontaneously hypertensive rats after neonatal sympathectomy

The effect of neonatal sympathectomy on vasodilator responses to acetylcholine (ACh) and cAMP has been studied in aortic rings of spontaneously hypertensive rats (SHR) and normotensive animals. The relaxation of intact SHR aorta in response to ACh and cAMP was 20-35% lower than that of normotensive rats. Sympathectomy in normotensive rats did not affect the level of blood pressure and aorta reactivity to Ach. In SHR, sympathectomy caused a decrease in blood pressure, while relaxation in response to ACh and cAMP increased, as compared to intact SHR, but remained lower than in normotensive rats. The data obtained suggest that the decrease in arterial pressure of sympathectomized SHR is a result not only of the reduction in sympathetic effects but also of the increase in smooth muscle relaxation.     

Ultrastructural characteristics of aortic endothelial cells in borderline hypertensive rats exposed to chronic social stress

Genetic predisposition and social stress may represent important risk factors in etiology of hypertension associated with endothelial dysfunction. Perturbations of endothelial structural integrity are also critical for the pathogenesis of vascular diseases. We examined effect of chronic social stress on structure of aortic endothelium in borderline hypertensive (BHR) and normotensive Wistar rats. Male BHR - offspring of Wistar mothers and SHR fathers and age-matched W were exposed to 6-week crowding stress (5 rats/cage, 200 cm2/rat). Aortic tissue was processed for electron microscopy and NO synthase activity measurement. Crowding stress significantly increased blood pressure in BHR compared to basal values (140+/-3 mm Hg vs. 130+/-3 mm Hg, p<0.05) and reduced enzyme activity by 37 % (p<0.01) in the aorta of BHR. Local slight structural alterations of endothelium were found in non-stressed BHR (p<0.001) when compared with Wistar rats. Chronic stress caused marked (p<0.005) subcellular injury of endothelial cells in aorta of BHR characterized by mitochondrial damage, presence of vacuoles, increased number of lysosomes, Weibel-Palade bodies, changes of intercellular connections and local disruption of endothelium, while only slight changes were seen in Wistar rats. Results suggest increased sensitivity of aortic endothelium of BHR to chronic crowding that may contribute to acceleration of arterial dysfunction.     

Upregulation of vascular NAD(P)H oxidase subunit gp91phox and impairment of the nitric oxide signal transduction pathway in hypertension

In this study we analyzed the role of vascular NAD(P)H oxidase in the generation of O(2)(-) and the endothelial impairment of NO signal transduction pathway in hypertension. In aortic rings of 15-month-old stroke-prone spontaneously hypertensive rats (SHR15) we found a 10-fold increased expression of NAD(P)H oxidase subunit gp91phox mRNA associated with a 3-fold increased production of O(2)(-) compared to age-matched Wistar rats (WIS15). Vasorelaxation studies in aortas of SHR15 showed a strongly diminished response to acetylcholine, NO-donor S-nitroso-N-acetyl-d,l-penicillamine, and organic nitrate glyceryl trinitrate compared to WIS15. Soluble guanylate cyclase (sGC) activity and sGC beta(1)-subunit protein expression was downregulated in aortas and lungs of SHR15. These data suggest an upregulation of vascular NAD(P)H oxidase and an impairment of the NO signal transduction pathway in hypertension.     

Vascular reactivity, tissue levels, and binding sites for endothelin: a comparison in the spontaneously hypertensive and Wistar-Kyoto rats.

The role of endothelin (ET-1) in mediating the development of blood pressure was investigated in the spontaneously hypertensive (SHR) rat using the Wistar-Kyoto (WKY) rat as the normotensive control. The following were characterized in both rat strains: age-dependent changes in mean arterial blood pressure (MAP), tissue (blood, lung, heart, and kidney) levels of immunoreactive ET-1 like related peptides (ET-1RP), aortic ring responses to ET-1, and specific high-affinity tissue (lung, atrium, ventricle, aorta, and kidney) binding sites for 125I-labelled ET-1. Commencing at age 10 weeks through to 12 weeks, SHR rats but not WKY rats developed a significant increase in MAP (from 152 +/- 7 to 189 +/- 3 mmHg) (1 mmHg = 133.32 Pa). However, in both WKY and SHR rats immunoreactive levels of ET-1RP increased (100 and 80%, respectively) throughout the same measurement period. The potency of ET-1 to contract aortic rings from SHR rats was slightly but not significantly greater than that for aortic rings from WKY rats, although aortic rings from SHR rats contracted in the presence of 0.5 nM ET-1, while those from WKY rats did not. The levels of immunoreactive ET-1RP were significantly reduced (32%) in the kidney and unchanged in the heart and lung of SHR rats compared with WKY rats. Specific 125I-labelled ET-1 binding sites displayed an increase and a significant decrease (24%) of density in the atrium and ventricle, respectively, a significant increase (31%) of affinity in the lung, and were unchanged in the kidney and aorta of SHR rats compared with WKY rats following the development of hypertension. The lack of a correlation between circulating levels of immunoreactive ET-1RP and the development of hypertension coupled with a lack of significant differences in vascular reactivity suggest that ET-1 is not the sole mediator of hypertension in this animal model. However, the tissue-specific changes in immunoreactive ET-1RP and 125I-labelled ET-1 binding sites suggest that ET-1 may be a partial mediator of hypertension and is subject to compensatory changes in response to the increased total peripheral resistance in SHR rats.     

Peritubular membrane potential in kidney proximal tubular cells of spontaneously hypertensive rats

Peritubular membrane potential in kidney proximal tubular cells of spontaneously hypertensive rats (SHR-Okamoto strain adult rats) was measured with conventional 3 mol KCl microelectrodes, in vivo. Peritubular cell membrane potential was not different in SHR (-66.5 ± 0.7 mV) as compared with normotensive control Wistar rats (-67.5 ± 1.2 mV). To test the effects of possible altered sodium membrane transport in SHR on proximal tubule peritubular membrane potential, we allowed SHR and control rats to drink 1% NaCl for two weeks. Again, proximal tubule peritubular membrane potential was not different in SHR on 1% NaCl (-67.0 ± 1.0 mV) as compared with control rats on 1% NaCl (-64.7 ± 1.3 mV). From these results we concluded that peritubular membrane potential in kidney proximal tubular cells of SHR was not different from normotensive Wistar control rats, and if some alteration of sodium transport in kidney proximal tubular cells of SHR could exist, that was not possible to evaluate from the measurements of peritubular membrane potential in kidney proximal tubular cells.     

Effect of nifedipine on calcium-induced contractions to potassium in the aorta and mesenteric arteries of spontaneously hypertensive and normotensive rats

Graded contractions to cumulative additions of calcium in the presence of KCl were obtained in strips of aorta and mesenteric arteries of normotensive (WKY) and spontaneously hypertensive (SHR) rats. In calcium-free medium, a maximally effective concentration of KCl produced a response that was larger in the mesenteric arteries (43-51% of control) than in the aorta (12-14% of control). The calcium channel blocker nifedipine (NFD, up to 10(-7) M) did not significantly alter these calcium-insensitive responses. The Ca2+-induced responses were inhibited by NFD, in a concentration-dependent fashion, in both vessel types of WKY and SHR rats. The aortic responses were more sensitive to inhibition by NFD than the responses of mesenteric arteries. Moreover, the aortic responses of WKY were inhibited to a greater extent than those of the SHR. The results suggest: (a) a differential calcium dependence of contractions to KCl in the vessels studied; (b) that aortic responses are dependent on NFD-sensitive voltage-sensitive Ca2+ channels to a greater extent than the responses of mesenteric arteries; and (c) that hypertension results in a decreased sensitivity of the aorta Ca2+ channels to NFD.     

Ca2(+)-sensitive K+ channel in aortic smooth muscle of rats

We measured K+ channel activity in inside-out patches of cell membrane from aortic vascular smooth muscle cultured (Passages 1-3) from Wistar, Wistar-Kyoto, and spontaneously hypertensive rats (SHR). With [Ca2+]i between 25 and 100 nm and 150 mm K+ on both sides of the membrane, the conductance of this channel was 55 +/- 7 pS (slope of current-voltage curve through 0 mV) and the current was outwardly rectified. There was no difference in single-channel conductance among the three rat strains. Increasing negative holding voltages or increasing [Ca2+]i, increased the probability of this type channel being open (Npo; P less than 0.01); SHR had a larger NPo (P less than 0.01). Compared with cells from Wistar and Wistar-Kyoto, cells from SHR also had the longest mean open time. The increased NPo and mean open time we observed in this K+ channel of cells from SHR could contribute, at least in part, to the increased membrane K+ permeability, reported previously.     

Vascular eicosanoid production in experimental hypertensive rats with different mechanisms

This study investigated the release of prostacyclin (PGI2) and thromboxane A2 (TXA2) from the aortic walls of various experimental hypertensive rats, e.g. spontaneously hypertensive rats (SHR), Dahl salt-sensitive (Dahl S) rats, deoxycorticosterone (DOCA)-salt hypertensive rats and renovascular (2-kidney, 1-clip (2K1C) and 1-kidney, 1-clip (1K1C] hypertensive rats. The PGI2 generation was increased significantly in these hypertensive models, irrespective of the hypertensive mechanisms, when they developed established hypertension. Dahl S rats, having an impaired PGI2 production on a low salt diet, restored PGI2 generating capacity to the control level of Dahl salt-resistant rats when they were fed a high salt diet and developed salt-induced hypertension. On the other hand, the TXA2 generation in the vascular walls was enhanced particularly in rat models for genetic hypertension, and this system was unaltered in the models for secondary hypertension, e.g. DOCA-salt and renovascular hypertension. Thus, it is suggested that the elevation of blood pressure is associated with an increase in vascular PGI2 production, and that the increased vascular TXA2 production is a characteristic feature of genetic hypertension.     

Increased vascular contractile sensitivity to serotonin in spontaneously hypertensive rats is linked with increased turnover of phosphoinositide

This study was conducted to determine if increased vascular contractile sensitivity to serotonin in spontaneously hypertensive (SHR) rats is linked with increased phosphoinositide turnover. Aortic and mesenteric artery rings from SHR exhibited 6.2- and 5.0-fold greater contractile sensitivity to serotonin than the aortic and mesenteric artery rings from normotensive Wistar-Kyoto (WKY) rats. Serotonin-induced turnover of phosphoinositide was measured by quantifying the accumulation of [3H] inositol labeled inositol monophosphate (IP), inositol bisphosphate (IP2) and inositol trisphosphate (IP3). Serotonin (3, 30, 200 microM) induced significantly greater accumulation of IP in SHR (279%, 590%, 895%) than in WKY (24%, 127%, 328%) aortic rings. Similarly, 3, 30 and 200 microM serotonin induced significantly greater accumulation of IP2 (118%, 241%, 451%) and IP3 (90%, 100%, 247%) in SHR than the accumulation of IP2 (15%, 58%, 122%) and IP3 (19%, 27%, 73%) in WKY aortic rings. Based on these data it is suggested that the greater vascular sensitivity to serotonin in SHR, at least in part, is attributable to increased turnover of phosphoinositide.     

Long-term effects of betamethasone on blood pressure and hypothalamo-pituitary-adrenocortical function in spontaneously hypertensive and normotensive rats

An enhanced hypothalamo-pituitary-adrenocortical (HPA) activity has been described during onset of elevated blood pressure in spontaneously hypertensive rats (SHR). An instability of the HPA axis could thus contribute to the development of hypertension in these animals. Glucocorticoid effects on blood pressure and HPA function were studied therefore in SHR and normotensive Wistar-Kyoto (WKY) and Wistar rats. Beginning at 4 weeks of age, the rats were treated with 0.1 and 0.5 microgram betamethasone per milliliter drinking water for 7 weeks. SHR and WKY responded with a significant elevation in average blood pressure. In SHR, mean blood pressure rose from 181.4 +/- 3.9 (mean +/- SEM) to 203.1 +/- 2.8 mm Hg in response to the lower dose of betamethasone and to 209.2 +/- 4.0 mm Hg in response to 0.5 microgram betamethasone per milliliter drinking water. In WKY, blood pressure increased from 134.4 +/- 3.3 to 148.2 +/- 3.0 and 157.9 +/- 4.5 mm Hg in response to the lower and higher dose of betamethasone, respectively. No significant effect was seen in Wistar rats, where the mean blood pressure values changed insignificantly from 133.8 +/- 2.1 to 136.3 +/- 3.2 and 135.6 +/- 2.4 mm Hg. Stress-induced secretion of corticosterone was significantly suppressed in a dose-dependent manner in all three strains. Stress-induced secretion of adrenocorticotropin was markedly reduced by 0.5 microgram betamethasone per milliliter in SHR and by both doses in WKY. No significant effect, however, was seen in Wistar rats. A predisposition to the hypertensiogenic actions of glucocorticoids was found therefore in SHR and WKY, but not in Wistar rats.     

Inhibitory effects of beta adrenoceptor antagonist, atenolol, on the thromboxane system in the kidney of spontaneously hypertensive rats

We attempted to investigate the alterations in the vasoconstrictor thromboxane (TXA2) system in the kidney when spontaneously hypertensive rats (SHR) were treated subchronically with atenolol, a beta 1-adrenoceptor antagonist. Atenolol treatment (30 mg/kg body weight per day for 2 weeks) reduced systolic blood pressure by 11%, being accompanied by a decrease in heart rate. This treatment strikingly decreased thromboxane content in the renal cortex by 48% (p less than 0.05), whereas the tissue content was unaltered for prostaglandin E2 (PGE2) or slightly decreased for prostacyclin (PGI2). These alterations in the eicosanoid system led to an increase in the ratio of PGE2/TXA2 and of PGI2/TXA2. Similarly, thromboxane content in the renal papilla was lowered significantly with atenolol treatment, which raised the ratio of PGE2 to TXA2. Thromboxane reduction was not observed in the aortic walls and heart. However, in the vascular walls, PGI2 synthesis was markedly stimulated with atenolol treatment, resulting in an increase in the ratio of PGI2 to TXA2. Thus, these data indicate that subchronic atenolol-treatment inhibits the thromboxane system in the kidney, thereby shifting the eicosanoid system towards a vasodilator state. These alterations contribute, in part, to the anti-hypertensive properties of atenolol in genetic hypertension.     

Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats

The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A2 (sPLA2-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA2-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 +/- 0.9%, n = 5; SHR+KH064 14.0 +/- 1.2%, n = 5) and interstitial (SHR 7.9 +/- 0.3%, n = 6; SHR+KH064 5.4 +/- 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 +/- 0.08, n = 12; SHR+KH064 3.09 +/- 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA2-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.